A facile synthesis and the asymmetric catalytic activity of BINOL-based thiazole (thiadiazole) thioether ligands

Article abstract of DOI:10.1016/j.jorganchem.2007.10.008

Four new BINOL-based thiazole (thiadiazole) thioether ligands (S)-1, (S)-2, (S,S)-3 and (S)-4 were prepared. When their catalytic effectiveness was tested, good results (up to 93% ee and 97% yield) were obtained in the asymmetric addition of diethylzinc to aldehydes while poor results were obtained in the asymmetric conjugate addition of diethylzinc to enones.

Full text of DOI:10.1016/j.jorganchem.2007.10.008

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Journal of Organometallic Chemistry 693 (2008) 17–22
www.elsevier.com/locate/jorganchem
A facile synthesis and the asymmetric catalytic activity of
BINOL-based thiazole (thiadiazole) thioether ligands
*
Zhi-Bing Dong, Bing Liu, Cao Fang, Jin-Shan Li
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
Received 2 August 2007; received in revised form 2 October 2007; accepted 5 October 2007
Available online 10 October 2007
Abstract
Four new BINOL-based thiazole (thiadiazole) thioether ligands (S)-1, (S)-2, (S,S)-3 and (S)-4 were prepared. When their catalytic
effectiveness was tested, good results (up to 93% ee and 97% yield) were obtained in the asymmetric addition of diethylzinc to aldehydes
while poor results were obtained in the asymmetric conjugate addition of diethylzinc to enones.
ꢀ 2007 Elsevier B.V. All rights reserved.
Keywords: BINOL; Diethylzinc; Titanium tetraisopropoxide; Copper trifluoromethanesulfonate; Asymmetric addition
1. Introduction
when combined with other donor atoms [6]. Despite of
the vast knowledge on sulfur-metal interactions in coordi-
nation chemistry [7], the use of chiral BINOL ligands con-
taining sulfur atoms in asymmetric catalysis appears to be
still rather undeveloped. Sulfur has somewhat less donor
and acceptor character. In addition to this electronic con-
sideration, the sulfur atom, in thioether ligands, for exam-
ple, has only two substituents which can create a less
hindered environment. Woodward [8] developed copper-
catalyzed asymmetric conjugate additions of various orga-
nometallic reagents to linear enones in the presence of
sulfur-containing BINOL ligands, and the sulfur atom
proved to be necessary in this reaction. Kang [9] reported
some BINOL-based ligands containing sulfur were effective
in promoting 1,4-additions of organometallics to various
enones. To the best of our knowledge, BINOL-based
ligands bounded with both sulfur-contained heterocycle
(thiazole or thiadiazole) and thioether block in which the
sulfur might serve as a talent anchor have never been
reported. Therefore, it should be of interest to explore
the catalytic ability of this kind of BINOL ligands. Herein,
we report the synthesis of new chiral ligands (S)-3-
(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl-BINOL [(S)-1],
(S)-3-(benzothiazol-2-ylthio)methyl-BINOL [(S)-2], (S,S)-
2,5-bis(2,20-dihydroxy-1,10-binaphthalen-3-yl)-1,3,4-thiadi-
azole [(S,S)-3], and (S)-3,30-bis[(5-methyl-1,3,4-thiadiazol-
In catalytic asymmetric systems, small changes in the
donating ability of a ligand or the size of a substituent
can have dramatic effect on the catalytic efficiency and
enantioselectivity [1]. 1,10-Binaphthol (BINOL) is one of
the most effective chiral ligands in asymmetric catalysis
[2]. Substituents at the 3-position of BINOL are normally
introduced via a two-step protocol that involves treatment
of a suitably protected BINOL with an organolithium
reagent, followed by reaction with an electrophile [3].
BINOL ligands substituted by the introduction of hetero-
aromatic groups at the 3 or 3,30-positions are less reported
[4]. In our previous research, some nitrogen-contained aro-
matic heterocycle groups such as 1,3,5-triazin-2-yl, 2-qui-
nolyl and 1,2,4-triazol-1-ylmethyl were, respectively,
introduced to the 3 or 3,30-positions of BINOL, and their
catalytic applicability in the addition of diethylzinc to alde-
hydes was also reported [5].
In recent years, chiral S-donor ligands have proved to be
useful as other classical asymmetric ligands, especially
*
Corresponding author. Fax: +86 22 2350 3627.
E-mail address: jinshan_li2001@yahoo.com.cn (J.-S. Li).
0022-328X/$ - see front matter ꢀ 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2007.10.008

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18
Z.-B. Dong et al. / Journal of Organometallic Chemistry 693 (2008) 17–22
2-ylthio)methyl]-BINOL [(S)-4] and their application in
asymmetric addition of diethylzinc to aldehydes in the
presence of titanium tetraisopropoxide and in asymmetric
conjugate addition of diethylzinc to enones in the presence
of Cu(OTf)2.
2. Results and discussion
The synthetic route for ligands (S)-1, (S)-2, (S,S)-3 and
(S)-4 is outlined in Scheme 1. (S)-5 was easily prepared by
the reaction of (S)-9 with 2-mercapto-5-methyl-1,3,4-thia-
diazole in high yield, and the corresponding target com-
pound (S)-1 was obtained after deprotection of the
MOM groups. Similarly, ligands (S)-2, (S,S)-3 and (S)-4
were synthesized in good yields.
S
S
N
N
N
S
S
Initially, we examined the titanium-catalyzed addition
reaction of benzaldehyde with diethylzinc using the four
chiral ligands. The active catalyst was formed in situ by
mixing the ligands with titanium tetraisopropoxide. The
molar ratio of Ti(OiPr)4/Et2Zn/benzaldehyde was set up
to be 1.2:3:1. The obtained results were summarized in
Table 1. Ligand (S,S)-3 gave the best result (95% yield
and 81% ee).
With the optimized conditions for benzaldehyde, the use
of ligand (S,S)-3 was extended to the asymmetric ethyla-
tion of other aromatic and a,b-unsaturated aldehydes
(Table 2). The additions were completed within 5 h at room
temperature with good yields and ee values for all the alde-
OH
OH
OH
OH
(S)-2
(S)-1
S
N
S
S
N
S
S
N
N
OH
OH
OH
OH
HO
HO
S
S
N
N
3
4
(S)-
(S
,S)-
S
N
N
S
e
a
OMOM
OMOM
(S)-1
98%
94%
(S
)-5
S
S
Br
N
OMOM
OMOM
e
b
(S)-2
OMOM
OMOM
85%
75%
(S
)-6
(S)-9
S
S
S
N
N
e
OMOM
OMOM
MOMO
MOMO
(S,S)-3
c
96%
95%
(S,S)-7
S
Cl
S
N
N
e
OMOM
OMOM
d
86%
OMOM
OMOM
(S)-4
89%
Cl
S
N
S
N
(S)-10
(S)-8
Scheme 1. Synthesis of (S)-1, (S)-2, (S,S)-3 and (S)-4. Reagents and conditions: (a) 1 equiv 2-mercapto-5-methyl-1,3,4-thiadiazole, KOH, reflux for 2 h;
(b) 1 equiv 2-mercaptobenzothiazole, KOH, reflux for 2 h; (c) 0.5 equiv 2, 5-dimercapto-1,3,4-thiadiazole, KOH, reflux for 2 h; (d) 2 equiv 2-mercapto-5-
methyl-1,3,4-thiadiazole, KOH, reflux for 2 h; (e) CH2Cl2, CH3OH, 6 M HCl, r.t.

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Z.-B. Dong et al. / Journal of Organometallic Chemistry 693 (2008) 17–22
Table 3
19
Table 1
Addition of diethylzinc (2 M in hexane) to benzaldehyde using ligands (S)-
1, (S)-2, (S,S)-3 and (S)-4 in the presence of titanium tetraisopropoxide
Asymmetric conjugate addition of Et2Zn to enones in the presence of
Cu(OTf)2
OH
O
O
Ti(OiPr)4/L*
PhMe
CHO
*
Cu(OTf)2 (0.05 eq.), Ligand(0.1eq.)
+
Et2Zn
*
Et2Zn (1.5 eq.), THF, 0 °C, 2 h
a
Entry
Ligand (mol%)
Yield (%)b
ee (%)c
Config.d
O
O
Cu(OTf)2 (0.05 eq.), Ligand(0.1eq.)
R: 4-ClPh
1
2
3
4
5
6
7
8
9
10
a
(S)-1 (20)
(S)-1 (10)
(S)-2 (20)
(S)-2 (15)
(S)-2 (10)
(S,S)-3 (20)
(S,S)-3 (15)
(S,S)-3 (10)
(S)-4 (20)
(S)-4 (10)
93
90
91
92
91
95
95
90
98
96
76
54
78
74
69
81
77
62
70
66
S
S
S
S
S
S
S
S
S
S
R
Ph
*
R
Ph
Et2Zn (1.5 eq.), THF, 0 °C, 2 h
Entry
Substrate
Liganda
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
a
Cyclohexenone
(S)-1
71
70
68
76
68
69
75
65
19d
19d
15d
33d
24e
26e
33e
11e
Cyclohexenone
(S)-2
Cyclohexenone
Cyclohexenone
(S,S)-3
(S)-4
4-Chloro-chalcone
4-Chloro-chalcone
4-Chloro-chalcone
4-Chloro-chalcone
(S)-1
(S)-2
(S,S)-3
(S)-4
Ti(OiPr)4/Et2Zn/benzaldehyde = 1.2:3:1; Reaction temperature: r.t.;
Reaction time: 5 h.
b
Ligand/Cu(OTf)2/Et2Zn/Substrate = 0.1: 0.05:1.5:1; Reaction tem-
Isolated yield.
c
perature: 0 ꢁC; Reaction time: 2 h.
Data were determined by GC analysis using a chiral column (Chiral
b
Isolated yield.
beta-DEX 120 capillary column).
d
c
The absolute configurations of the products were not determined.
Data were determined by GC analysis using a chiral column (Chiral
The absolute configurations of the products were determined by
comparison to the literature data.
d
GAMA-DEX 225 capillary column).
e
Data were determined by HPLC (Chiracel OJ-H column).
hydes. The best enantioselectivity up to 93% ee was
obtained with o-methoxybenzaldehyde (Entry 5).
Table 4
Furthermore, the effectiveness of the four ligands in the
copper-catalyzed conjugate addition of diethylzinc to
enones was tested. Cyclohexenone and 4-chloro-chalcone
were chosen as typical substrates of cyclic and acyclic
enones, respectively. The conjugate addition of diethylzinc
to enones were carried out in the presence of Cu(OTf)2
(5 mol%) and chiral ligand (10 mol%) in THF at 0 ꢁC
for 2 h producing 3-ethyl ketones. The obtained results
are summarized in Table 3. (S)-4 gave the best result when
cyclohexenone was the substrate while (S,S)-3 was the best
ligand when 4-chloro-chalcone was the substrate. With
Asymmetric conjugate addition of Et2Zn to acyclic enones using ligand
(S,S)-3 in the presence of Cu(OTf)2
O
Cu(OTf)2 (0.05 eq.), (S,S)-3 (0.1eq.)
O
R
Ph
*
R
Ph
Et2Zn (1.5 eq.), THF, 0
°
C, 2 h
Yield (%)b
Entry
Ra
ee (%)c
1
2
3
a
Ph
4-MeOPh
4-Cl
62
60
75
13
10
33
(S,S)-3/Cu(OTf)2/Et2Zn/Substrate = 0.1:0.05:1.5:1; Reaction temper-
ature: 0 ꢁC; Reaction time: 2 h.
b
Isolated yield.
c
Data were determined by HPLC (Chiracel OJ-H column). The
Table 2
absolute configurations of the products were not determined.
Addition of diethylzinc (2 M in hexane) to aldehydes using ligand (S,S)-3
in the presence of titanium tetraisopropoxide
Ti(OiPr)4/(S,S)-3
OH
*
ligand (S,S)-3, various chalcones were converted into the
corresponding chiral ketones (Table 4). The results
showed that the electron-withdrawing substituent of the
chalcone obviously increased the enantioselectivity and
the yield (entry 3) while the electron-donating group
slightly decreased the enantioselectivity and the yield
(entry 2).
O
+
Et2Zn
PhMe
Yield (%)b
R
R
H
Entry
Ra
ee (%)c
Config.d
1
2
3
4
5
6
7
a
Ph
95
94
95
91
97
94
92
81
89
91
87
93
87
86
S
S
S
S
S
S
S
p-ClC6H4
p-BrC6H4
p-MeOC6H4
o-MeOC6H4
PhCH@CH
1-Naphthyl
3. Conclusion
(S,S)-3/Ti(OiPr)4/Et2Zn/aldehyde = 0.2:1.2:3:1; Reaction temperature:
In conclusion, we prepared four new chiral modified
BINOL ligands (S)-1, (S)-2, (S,S)-3 and (S)-4. It was found
that the four chiral ligands could catalyze both the asym-
metric addition of diethylzinc to aldehydes and the asym-
metric conjugate addition of diethylzinc to enones. The
titanium complex of (S,S)-3 was found to be an efficient
r.t.; Reaction time: 5 h.
b
Isolated yield.
c
Data were determined by GC analysis using a chiral column (Chiral
beta-DEX 120 capillary column).
d
The absolute configurations of the products were determined by
comparison to the literature data.

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Z.-B. Dong et al. / Journal of Organometallic Chemistry 693 (2008) 17–22
catalyst in the asymmetric addition of diethylzinc to alde-
hydes. Poor enantioselectivities were obtained when the
four ligands were applied in the asymmetric conjugate
addition of diethylzinc to enones in the presence of
Cu(OTf)2.
125.17, 124.95, 124.42, 124.21, 123.63, 121.56, 121.40,
120.94, 117.25, 116.53, 99.45, 94.95, 56.93, 55.96, 33.30.
HR-MS Calc. for C32H28NO4S2 (M+ + H): 554.1454.
Found: 554.1452.
4.1.3. (S,S)-2,5-Bis{[2,20-bis(methoxymethoxy)-1,10-
binaphthyl-3-yl]methylthio}-1,3,4-thiadiazole [(S,S)-7]
4. Experimental
25
Yellow solid. Yield: 95%, m.p. 90–92 ꢁC. ½aꢀD = ꢁ41.9
1
4.1. General
(c = 5.57, CHCl3). H NMR (300 MHz, CDCl3) d: 8.12–
7.16 (m, 22H), 5.09 (dd, J = 11.10, 4H), 4.90 (s, 4H), 4.65
(d, J = 5.70, 2H), 4.52 (d, J = 5.40, 2H), 3.19 (d,
J = 3.00, 6H), 3.06 (d, J = 3.00, 6H). 13C NMR
(75 MHz, CDCl3) d: 165.37, 162.35, 152.88, 152.63,
133.86, 130.73, 130.31, 130.07, 129.69, 129.55, 127.97,
126.91, 126.51, 125.78, 125.63, 125.43, 125.28, 124.24,
120.39, 116.45, 99.46, 94.90, 56.98, 56.05, 34.41, 22.69.
HR-MS Calc. for C52H47N2O8S3 (M+ + H): 923.2489.
Found: 923.2483.
The 1H and 13C NMR spectra were recorded on a
Bruker AC-300 instrument in CDCl3 solution with
TMS as internal standard. Optical rotations were mea-
sured on a Perkin–Elmer 241 polarimeter. The high-reso-
lution mass spectra (MALDI-HRMS) were measured on
an Ionspec FT MS 7.0T spectrometer. All experiments
which are sensitive to moisture or air were carried out
under an argon atmosphere using standard Schlenk tech-
niques. Diethylzinc (2 M in hexane) was purchased from
Aldrich. All anhydrous solvents were purified and dried
by standard techniques just before use. (S)-9 [10] and
(S)-10 [11] were prepared according to the literature
method, respectively.
4.1.4. (S)-3,30-Bis[(5-methyl-1,3,4-thiadiazol-2-
ylthio)methyl]-2, 20-bis(methoxymethoxy)-1,10-
binaphthalene [(S)-8]
Yellow solid. Yield: 86%, m.p. 154–156 ꢁC.
25
½aꢀD = ꢁ38.5 (c = 0.41, CHCl3). 1H NMR (300 MHz,
4.1.1. (S)-3-(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl-
2,20-bis(methoxymethoxy)-1,10-binaphthalene [(S)-5]
[Typical procedure for the synthesis of (S)-5, (S)-6,
(S,S)-7 and (S)-8]
CDCl3) d: 8.16 (s, 2H), 7.86 (d, J = 8.10, 2H), 7.43–7.12
(m, 6H), 4.90 (s, 4H), 4.58 (d, J = 5.70, 2H), 4.50 (d,
J = 6.00, 2H), 3.03 (s, 6H), 2.73 (s, 6H). 13C NMR
(75 MHz, CDCl3) d: 165.30, 165.05, 162.34, 152.79,
133.88, 130.87, 130.58, 129.98, 128.06, 126.93, 125.89,
125.40, 125.32, 99.43, 56.98, 33.97, 15.63. HR-MS
Calc. for C32H31N4O4S4 (M+ + H): 663.1223. Found:
663.1226.
To a solution of (S)-9 (1.868 g, 4 mmol) in 20 mL dry
ethanol was added 2-mercapto-5-methyl-1,3,4-thiadiazole
(0.528 g, 4 mmol) and KOH (0.224 g, 4 mmol). The reac-
tion process was monitored by TLC. After refluxing for
2 h, the reaction mixture was concentrated and washed
with water. The oil layer was extracted with ethyl acetate
(3 · 20 mL) and dried over anhydrous MgSO4. After evap-
oration of the volatiles, the residue was purified by column
chromatography on silica gel (hexane/ethyl acetate 3:1) to
give (S)-5 (1.95 g, 94% yield) as a white solid. M.p.
4.1.5. (S)-3-(5-Methyl-1,3,4-thiadiazol-2-ylthio)methyl-
BINOL [(S)-1] (Typical procedure for the deprotection
of the MOM groups)
To a solution of (S)-5 (0.518 g, 1 mmol) in CH2Cl2
(10 mL) and MeOH (20 mL) was added 6 M HCl (5 mL)
and the mixture was stirred at room temperature for
12 h. The mixture was poured into water (40 mL),
extracted with CH2Cl2, washed with water and saturated
NaHCO3, dried over anhydrous MgSO4 and finally con-
centrated in vacuo to give a white solid. Yield: 98%, m.p.
25
112 ꢁC. ½aꢀD = ꢁ47.7 (c = 2.83 THF). 1H NMR
(300 MHz, CDCl3) 8.12–7.14 (m, 11H), 5.09 (dd,
J = 18.00, 2H), 4.90 (s, 2H), 4.65 (d, J = 5.70, 1H), 4.53
(d, J = 5.70, 1H), 3.19 (s, 3H), 3.06 (s, 3H), 2.73 (s, 3H).
13C NMR (75 MHz, CDCl3) d: 165.57, 162.39, 152.88,
152.62, 133.80, 130.71, 130.27, 130.03, 129.67, 127.94,
126.85, 126.44, 125.69, 125.42, 125.21, 124.21, 116.46,
99.44, 94.92, 56.96, 56.03, 34.13, 15.66. HR-MS Calc. for
C28H27N2O4S2 (M++H): 519.1407. Found: 519.1402.
25
208–210 ꢁC. ½aꢀD = ꢁ97.1 (c = 0.48, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 8.11 (s, 1H), 7.99–7.85 (m, 3H),
7.40–7.10 (m, 7H), 6.33 (s, 1H), 5.10 (s, 1H), 4.80 (s, 2H),
2.70 (s, 3H). 13C NMR (75 MHz, CDCl3) d: 165.26,
162.35, 152.61, 151.21, 133.44, 133.35, 131.78, 131.19,
129.42, 129.07, 128.37, 128.30, 127.48, 127.30, 125.57,
124.34, 123.88, 117.91, 112.67, 111.64, 33.50, 15.62. HR-
MS Calc. for C24H19N2O2S2 (M+ + H): 431.0883. Found:
431.0861.
4.1.2. (S)-3-(Benzothiazol-2-ylthio)methyl-2,20-
bis(methoxymethoxy)-1,10-binaphtha-lene [(S)-6]
25
Semi-solid. yield: 85%, ½aꢀD = ꢁ75.1 (c = 3.34, CHCl3).
1H NMR (300 MHz, CDCl3) d: 8.18 (s, 1H), 7.99–7.14
(m, 14H), 5.09 (dd, J = 19.05, 2H), 4.98 (s, 2H), 4.70 (d,
J = 5.7, 1H), 4.57 (d, J = 5.4, 1H), 3.18 (s, 3H), 3.05 (s,
3H). 13C NMR (75 MHz, CDCl3) d: 162.35, 153.21,
152.92, 150.19, 133.88, 130.27, 130.18, 130.01, 129.71,
128.86, 128.03, 127.81, 126.84, 126.04, 125.72, 125.50,
4.1.6. (S)-3-(Benzothiazol-2-ylthio)methyl-BINOL
[(S)-2]
White solid. Yield: 75%, m.p. 102–104 ꢁC.
25
½aꢀD = ꢁ105.8 (c = 2.17, CHCl3). 1H NMR (300 MHz,